1. Field of the Invention
This invention relates to a process for preparing therapeutic compositions containing nanoparticles.
2. Reported Developments
Bioavailability is the degree to which a drug becomes available to the target tissue after administration. Many factors can affect bioavailability including the dosage form and various properties, e.g., dissolution rate of the drug. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is poorly soluble in water. Poorly water soluble drugs, i.e., those having a solubility less than about 10 mg/ml, tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation. Moreover, poorly water soluble drugs tend to be unsafe for intravenous administration techniques, which are used primarily in conjunction with fully soluble drug substances.
It is known that the rate of dissolution of a particulate drug can increase with increasing surface area, i.e., decreasing particle size. Consequently, methods of making finely divided drugs have been studied and efforts have been made to control the size and size range of drug particles in pharmaceutical compositions. For example, dry milling techniques have been used to reduce particle size and hence influence drug absorption. However, in conventional dry milling, as discussed by Lachman et al, The Theory and Practice of Industrial Pharmacy, Chapter 2, "Milling", p. 45, (1986), the limit of fineness is reached in the region of 100 microns (100,000 nm) when material cakes on the milling chamber. Lachman et al note that wet grinding is beneficial in further reducing particle size, but that flocculation restricts the lower particle size limit to approximately 10 microns (10,000 nm). However, there tends to be a bias in the pharmaceutical art against wet milling due to concerns associated with contamination. Commercial airjet milling techniques have provided particles ranging in average particle size from as low as about 1 to 50 .mu.m (1,000-50,000 nm). However, such dry milling techniques can cause unacceptable levels of dust.
Other techniques for preparing pharmaceutical compositions include loading drugs into liposomes or polymers, e.g., during emulsion polymerization. However, such techniques have problems and limitations. For example, a lipid soluble drug is often required in preparing suitable liposomes. Further, unacceptably large amounts of the liposome or polymer are often required to prepare unit drug doses. Further still, techniques for preparing such pharmaceutical compositions tend to be complex. A principal technical difficulty encountered with emulsion polymerization is the removal of contaminants, such as unreacted monomer or initiator, which can be toxic, at the end of the manufacturing process.
U.S. Pat. No. 4,540,602 (Motoyama et al) discloses a solid drug pulverized in an aqueous solution of a water-soluble high molecular substance using a wet grinding machine. However, Motoyama et al teach that as a result of such wet grinding, the drug is formed into finely divided particles ranging from 0.5 .mu.m (500 nm) or less to 5 .mu.m (5,000 nm) in diameter.
EPO 275,796 describes the production of colloidally dispersible systems comprising a substance in the form of spherical particles smaller than 500 nm. However, the method involves a precipitation effected by mixing a solution of the substance and a miscible non-solvent for the substance and results in the formation of non-crystalline nanopanicles. Furthermore, precipitation techniques for preparing particles tend to provide particles contaminated with solvents. Such solvents are often toxic and can be very difficult, if not impossible, to adequately remove to pharmaceutically acceptable levels to be practical.
U.S. Pat. No. 4,107,288 describes particles in the size range from 10 to 1,000 nm containing a biologically or pharmacodynamically active material. However, the particles comprise a crosslinked matrix of macromolecules having the active material supported on or incorporated into the matrix.
U.S. Pat. No. 5,145,684 discloses a process for preparing particles consisting of a crystalline drug substance having a surface modifier or surface active agent adsorbed on the surface of the particles in an amount sufficient to maintain an average particle size of less than about 400 nanometers. The process of preparation comprises the steps of dispersing the drug substance in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size of the drug substance to an average particle size of less than 400 nm. The particles can be reduced in the presence of a surface active agent or, alternatively, the particles can be contacted with a surface active agent after attrition. The presence of the surface active agent prevents flocculation/agglomeration of the nanoparticles.
The mechanical means applied to reduce the particle size of the drug substance is a dispersion mill, the variety of which include a ball mill, an attrition mill, a vibratory mill and media mill, such as sand mill, and a bead mill.
The grinding media for the particle size reduction is spherical or particulate in form and includes: ZrO.sub.2 stabilized with magnesia, zirconium silicate, glass, stainless steel, titania, alumina and ZrO.sub.2 stabilized with yttrium. Processing time of the sample can be several days long. This patent is incorporated herein in its entirety by reference.
To a more limited extent the prior art also utilized microfluidizers for preparing small particle-size materials in general. Microfluidizers are relatively new devices operating on the submerged jet principle. In operating a microfluidizer to obtain nanoparticulates, a premix flow is forced by a high pressure pump through a so-called interaction chamber consisting of a system of channels in a ceramic block which split the premix into two streams. Precisely controlled shear, turbulent and cavitational forces are generated within the interaction chamber during microfluidization. The two streams are recombined at high velocity to produce shear. The so-obtained product can be recycled into the microfluidizer to obtain smaller and smaller particles.
The prior an has reported two distinct advantages of microfluidization over conventional milling processes (such as reported in U.S. Pat. No. 5,145,684, supra): substantial reduction of contamination of the final product, and the ease of production scaleup.
Numerous publications and patents were devoted to emulsions, liposomes and/or microencapsulated suspensions of various substances including drug substances produced by the use of microfluidizers. See, for example:
1) U.S. Pat. No. 5,342,609, directed to methods of preparing solid apatite particles used in magnetic resonance imaging, x-ray and ultrasound. PA1 2) U.S. Pat. No. 5,228,905, directed to producing an oil-in-water dispersion for coating a porous substrate, such as wood. PA1 3) U.S. Pat. No. 5,039,527 is drawn to a process of producing hexamethylmelamine containing parenteral emulsions. PA1 4) G. Gregoriadis, H. Da Silva, and A. T. Florence, "A Procedure for the Efficient Entrapment of Drugs in Dehydration-Rehydration Liposomes 0DRVs), Int. J. Pharm. 65, 235-242 (1990). PA1 5) E. Doegito, H. Fessi, M. Appel, F. Puisieux, J. Bolard, and J. P. Devissaguet, "New Techniques for Preparing Submicronic Emulsions--Application to Amphotericine-B,: STP Pharma Sciences 4, 155-162 (1994). PA1 6). M. Lidgate, R. C. Fu, N. E. Byars, L. C. Foster, and J. S. Fleitman, "Formulation of Vaccine Adjuvant Muramyldipeptides. Part 3. Processing Optimization, Characterization and Bioactivity of an Emulsion Vehicle," Pharm Res. 6, 748-752 (1989). PA1 7) H. Talsma, A. Y. Ozer, L. VanBloois, and D. J. Crommelin, "The Size Reduction of Liposomes with a High Pressure Homogenizer (Microfluidizer): Characterization of Prepared Dispersions and Comparison with Conventional Methods," Drug Dev. Ind. Pharm. 15, 197-207 (1989). PA1 8) D. M. Lidgate, T. Tranner, R. M. Shultz, and R. Maskiewicz, "Sterile Filtration of a Parenteral Emulsion," Pharm. Res. 9, 860-863 (1990). PA1 9) R. Bodmeier, and H. Chen, "Indomethacin Polymeric Nanosuspensions Prepared by Microfluidization," J. Contr. Rel. 12, 223-233 (1990). PA1 10) R. Bodmeier, H. Chen, P. Tyle, and P. Jarosz, "Spontaneous Formation of Drug-Containing Acrylic Nanoparticles," J. Microencap, 8, 161-170 ( 1991). PA1 11) F. Koosha, and R. H. Muller, "Nanoparticle Production by Microfluidization," Archiv Der Pharmazie 321,680 (1988). PA1 a) dispersing a crystalline drug substance in a liquid dispersion medium containing a surface modifier, and PA1 b) subjecting the liquid dispersion medium to the comminuting action of a microfluidizer asserting shear, impact and cavitation forces onto the crystalline drug substance contained in the liquid dispersion medium for a time necessary to reduce the mean particle size of said crystalline drug substance to less than 400 nm.
However, reports are few on reducing mean particle size (hereinafter sometimes abbreviated as MPS) of water-insoluble materials for use in pharmaceutical/diagnostic imaging compositions.
The present invention is directed to a process incorporating the advantages of microfluidizer process over conventional milling processes along with utilizing formulation and/or process parameters necessary for successful particle size reduction of a pharmaceutical suspension.
The primary forces attributed to microfluidization for producing either emulsions or dispersions, and for reducing the MPS of water-insoluble materials include: shear, involving boundary layers, turbulent flow, acceleration and change in flow direction; impact, involving collision of solid elements and collision of particles in the chamber of microfluidizer; and cavitation, involving an increased change in velocity with a decreased change in pressure and turbulent flow. An additional force can be attributed to conventional milling processes of attrition, i.e., grinding by friction. In reference to conventional milling process it is understood that the process involves the use of gravity, attrition and/or media mills, all containing a grinding media.